A new study shows that a surprising phenomenon--sensitivity to repeated cocaine exposure--can now be added to the short list of activities linked to genes controlling the biological clock.

Researchers funded by the National Institutes of Health (NIH) unearthed the unexpected connection between circadian rhythms in insects and cocaine sensitization, a behavior that occurs in both fruit flies and vertebrates and that has been linked to drug addiction in humans.

In the August 13 issue of Science, Dr. Jay Hirsh and his coworkers Rozi Andretic and Sarah Chaney at the University of Virginia report that fruit flies missing several genes that play a critical role in the insects' internal biological clock did not become sensitized to cocaine, a process in which repeated doses of the drug produce increasingly severe responses.

"This opens up the field of drug studies to thinking about how a totally unexpected set of genes functions in response to drugs," said Dr. Hirsh, the senior author of the report.

Besides enabling the potential development of drugs to treat cocaine addiction, this research holds out the prospect that so-called "clock" genes--which are involved in setting and maintaining the body's internal clock--might have other, as yet undiscovered, roles in the body and brain.

"These important findings illustrate that the clock genes perform other important roles in regulating the physiology of fruit flies, and likely humans," said Dr. Michael Sesma, a neurobiologist at the National Institute of General Medical Sciences, an NIH component that funded the study along with NIH's National Institute on Drug Abuse.

Fruit flies--recognized by many people as unwanted sentinels of overripe bananas--are an extraordinary laboratory tool. Nearly a century of genetic research on fruit flies now permits biologists to mix and match fly genes to probe the function of physiological processes such as nervous system pathways. Importantly, many of the genes discovered in flies and other simple organisms have molecular cousins in humans, and the pathways linking these genes are also very similar across species spanning vast amounts of evolutionary time.

"Because of the genetic similarities in fruit flies and humans, fruit flies can serve as a valuable model to study the complex biological factors underlying drug abuse. This exciting new research has given us a clue to the specific genetic mechanisms that influence vulnerability to addiction. Once clear, these mechanisms could become the basis for predicting who is most at risk for addiction and thus become a major aid in preventing this national health problem," said Dr. Alan I. Leshner, director of the National Institute on Drug Abuse.

For the past several years, Dr. Hirsh has used insect model systems to probe some of the brain's molecular mysteries, such as the circuitry involved in learning, memory, and muscle movement. While researching core communications pathways in the nervous systems of fruit flies, Dr. Hirsh and his colleagues reasoned that cocaine--which hijacks key elements of these communications systems--might be a valuable tool to study the molecular underpinnings of cocaine-induced behavior and addiction.

Last year, the team hit pay dirt, showing that normal fruit flies develop a heightened response to repeated doses of cocaine. The work laid the foundation for further studies elaborating the possible molecular bases for cocaine addiction in people, including the present work and other recently published findings in the current online issue of Current Biology, that implicate tyramine, one of the body's naturally occurring molecules, as the likely perpetrator of cocaine sensitization in fruit flies.

Researchers studying drug addiction or circadian rhythms yearn to understand the molecular actors playing key roles in these and other functions of the brain. The new work should lead the way toward unlocking the secrets behind some of the most basic of humans' and animals' activities--why heart attacks are more likely to strike in the morning and asthma is more likely to occur at night, what makes animals hibernate every winter and how babies know to wake up at precisely the same time each morning, and perhaps even why the summertime drone of cicadas reaches such an uproarious peak every 17 years.

For scientific perspective on this work, contact either the NIGMS Office of Communications and Public Liaison (301/496-7301) to interview Dr. Michael Sesma, program director in NIGMS' Division of Genetics and Developmental Biology; or the NIDA Public Information and Liaison Branch (301/443-6245) to interview Dr. Jonathan Pollack, program director in NIDA's Division of Basic Research.